(1) Field of the Invention
The present invention relates to the preparation of the 5(S)-(2′-hydroxyethoxy)-20(S)-camptothecin diastereoisomer of camptothecin and its use for the treatment of cancer.
(2) Description of the Related Art
Camptothecin (CPT) is a pentacyclic plant alkaloid first isolated from the Chinese tree Camptotheca acuminate by Wall et al., J. Am. Chem. Soc., 88: 3888 (1966). The structure of camptothecin is shown in formula I:

Without modification, camptothecin is highly lipophilic and poorly water soluble. Early clinical trials using sodium camptothecin solubilized by sodium hydroxide in water showed that the compound had antineoplastic activity, and further research demonstrated that the activity was due to the action of the compound as an inhibitor of DNA topoisomerase I. However, the therapeutic potential of camptothecin has thus far failed to be fully realized on account of toxicity problems and limited water solubility.
Attempts to provide improved properties for this compound have included the synthesis and testing of numerous analogues of camptothecin. For example, U.S. Pat. No. 5,004,758 describes water soluble camptothecin analogues, U.S. Pat. No. 5,734,056 describes camptothecin analogues. Topotecan, an analogue of camptothecin, is discussed in U.S. Pat. No. 5,004,758, and U.S. Patent Publication US 2007/0105885.
Various Carbon-5 substituted analogues of 20(S)-camptothecin are described in U.S. Pat. No. 6,177,439. One such analogue, 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin has the structure shown in formula II:
The U.S. Pat. No. 6,177,439 discloses processes for the preparation of the diastereoisomeric mixture of this analogue—referred to herein as 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin, or as 5-(2′-hydroxyethoxy)-20(S)-camptothecin.
5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin is a 5-alkoxy substituted 20(S)-camptothecin analog having a pentacyclic structure. It has chiral centers at Carbon-5 and Carbon-20 positions. The Carbon-20 chiral center corresponds to the natural S-configuration. However, the Carbon-5 substitution represents both R and S diastereoisomers in an approximately equal ratio. The molecular formula of 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin is C22H20N2O6. The compound has a molecular weight of 408.41 g/mole and a melting point of 190° C. The diastereoisomeric mixture 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin, which can also be referred to as 5-(2′-hydroxyethoxy)-20(S)-camptothecin has poor water solubility.
The 5(S)-(2′-hydroxyethoxy)-20(S)-camptothecin diastereomer of 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin is described chemically as 5(S)-(2-hydroxyethoxy)-20(S)-camptothecin, whereas the 5(R)-(2′-hydroxyethoxy)-20(S)-camptothecin diastereomer of 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin is described chemically as 5(R)-(2′-hydroxyethoxy)-20(S)-camptothecin. 5(S)-(2′-hydroxyethoxy)-20(S)-camptothecin is also chemically described as 4-(S)-Ethyl-4-hydroxy-12(S)-(2-hydroxyethoxy)-1,12-dihydro-4H-2-oxa-6,12a-diazadibenzo[b,h]fluorene-3,13-dione, which has the following chemical structure shown in formula III:

5(R)-(2′-hydroxyethoxy)-20(S)-camptothecin has the chemical structure shown in formula IV.

Generally speaking, isomers that are enantiomers have, when present in a symmetric environment, identical chemical and physical properties except for their ability to rotate plane-polarized light by equal amounts but in opposite directions. On the other hand, isomers that are diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers. Diastereomers can, and most often do, have different physical properties and different reactivity. In another definition diastereomers are pairs of isomers that have opposite configurations at one or more of the chiral centers but are not mirror images of each other.
Thus, it is clear from the foregoing that it would be desirable to provide the benefits of camptothecin in the treatment of cancer while reducing or avoiding one or more of the undesirable side effects or disadvantages that has heretofore limited its usefulness.